Is ROGDI p.Gly175Ser (c.523G>A) pathogenic?

ROGDI p.Gly175Ser (c.523G>A) is classified Uncertain significance in ROGDI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-28). AlphaMissense: likely benign (0.0753); Very rare (popmax 0.00918%, eas); Associated with Inborn genetic diseases.

What condition is associated with ROGDI p.Gly175Ser (c.523G>A)?

ROGDI p.Gly175Ser (c.523G>A) is associated with Inborn genetic diseases, amelocerebrohypohidrotic syndrome (ClinVar).

How common is ROGDI p.Gly175Ser (c.523G>A) in the general population?

ROGDI p.Gly175Ser (c.523G>A) is very rare (popmax 0.00918%, eas) (gnomAD).

What do computational predictors say about ROGDI p.Gly175Ser (c.523G>A)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

ROGDI p.Gly175Ser

c.523G>A · rs376116493 · VCV850441

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00918%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -4.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.35	unconstrained · MANE · 5,108 bp · p 7.6e-12 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00918% East Asian · 4/43,586 alleles

Filtering AF 0.00496% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00539% 84/1,557,820 alleles · very rare exomes 68/1,405,648 · genomes 16/152,172 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00918%	10,896
African / African-American	0.00806%	12,401
European (non-Finnish)	0.00613%	16,301
Remaining individualsnot grpmax-eligible	0.00494%	20,243

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ROGDI
Protein: p.Gly175Ser
Coding: c.523G>A
MANE Select: NM_024589
dbSNP: rs376116493
Type: single nucleotide variant
Location: chr16:4798577 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.59 · 2 PDB
Residue 175: a UniProt-annotated variant site (in ktzs; uncertain significance); a UniProt-annotated variant site (in ktzs)

Full ROGDI gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amelocerebrohypohidrotic syndrome

Similar variants

ROGDI p.Gly175= Likely benign ★ same residue
ROGDI c.117+1G>A Pathogenic/Likely pathogenic ★★ same condition
ROGDI c.46-2A>G Likely pathogenic ★★ same condition
ROGDI c.531+5G>C Likely pathogenic ★★ same condition
ROGDI c.645+2T>A Likely pathogenic ★★ same condition
ROGDI p.Arg157Ter Pathogenic ★★ same condition
ROGDI p.Gln112Ter Pathogenic/Likely pathogenic ★★ same condition
ROGDI p.Gln114Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rogdi-p-gly175ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown